Coronaviruses

Etiology

Coronaviruses are enveloped viruses of medium to large size (80-220 nm) that possess the largest known single-stranded positive-sense RNA genomes. These viruses encode the protein nsp14-ExoN, which is the first known RNA proofreading enzyme and is likely responsible for the evolution of the large and complex coronavirus genome. Coronaviruses derive their name from the characteristic surface projections of the spike protein, giving a corona or crown-like appearance on negative-stain electron microscopy. Coronaviruses are organized taxonomically by a lettering system based on genomic phylogenetic relationships. Alphacoronaviruses include HCoV-229E and HCoV-NL63. Betacoronaviruses include four human pathogens and are commonly divided into four lineages, without formal taxonomic recognition. HCoV-OC43 and HCoV-HKU1 are in lineage A, whereas SARS-CoV falls in lineage B. Lineages C and D were exclusively comprised of bat coronaviruses until the discovery of MERS-CoV, which aligns with lineage C. Gammacoronaviruses and deltacoronaviruses presently include exclusively nonhuman pathogens.

Coronaviruses received international attention during the SARS outbreak, which was responsible for more than 800 deaths in 30 countries. SARS-CoV, a novel coronavirus at the time of the epidemic, was found to be the causative agent of SARS. The detection of SARS-like coronaviruses in a live animal market in the Guangdong province in Southern China, along with serologic evidence of exposure in food handlers in the same market, suggest that these markets may have facilitated the spread of SARS-CoV to humans from an animal reservoir. Subsequent studies identified SARS-like coronaviruses in fecal specimens from asymptomatic Chinese horseshoe bats that are very closely related, but not direct precursors to, SARS-CoV and are capable of infecting human cells. Thus, although bats are a reservoir for SARS-CoV-like precursors, the precise antecedent to SARS-CoV remains to be identified.

Another novel coronavirus, MERS-CoV, was isolated from a man with acute pneumonia and renal failure in Saudi Arabia. As of March 1, 2017, the WHO had recorded nearly 2000 confirmed cases of MERS, with nearly 700 deaths worldwide (~35% mortality rate). MERS-CoV differs from SARS in that it seems to be less communicable, although human-to-human transmission has been documented. MERS-CoV uses dipeptidyl peptidase 4 and carcinoembryonic antigen–like cell-adhesion molecule 5 as its cellular and co-receptor, respectively; SARS-CoV utilizes ACE-2. With this receptor specificity, MERS-CoV can infect cells from several animal lineages, including human, pig, and bat, suggesting the possibility of movement between multiple species.

Epidemiology

Seroprevalence studies have demonstrated that antibodies against 229E and OC43 increase rapidly during early childhood, so that by adulthood 90–100% of persons are seropositive. Although less information is available for HKU1 and NL63, available studies demonstrate similar patterns of seroconversion to these viruses during early childhood. Although some degree of strain-specific protection may be afforded by recent infection, reinfections are common and occur despite the presence of strain-specific antibodies. Attack rates are similar in different age-groups. Although infections occur throughout the year, there is a peak during the winter and early spring for each of these HCoVs. In the United States, outbreaks of OC43 and 229E have occurred in 2- to 3-yr alternating cycles. Independent studies of viral etiologies of upper and lower respiratory infections during the same period, but from different countries, have confirmed that all known HCoVs have a worldwide distribution. Studies using both viral culture and polymerase chain reaction (PCR) multiplex assays demonstrate that coronaviruses often appear in coinfections with other respiratory viruses, including respiratory syncytial virus, adenovirus, rhinovirus, and human metapneumovirus. Volunteer studies demonstrated that OC43 and 229E are transmitted predominantly through the respiratory route. Droplet spread appears to be most important, although aerosol transmission may also occur.

There have been no identified natural or laboratory-acquired cases of SARS-CoV since 2004, but the mechanisms of introduction, spread, and disease remain important for potential animal-to-human transmission and disease. The primary mode of SARS-CoV transmission occurred through direct or indirect contact of mucous membranes with infectious droplets or fomites. Aerosol transmission was less common, occurring primarily in the setting of endotracheal intubation, bronchoscopy, or treatment with aerosolized medications. Fecal-oral transmission did not appear to be an efficient mode of transmission, but may have occurred because of the profuse diarrhea observed in some patients. The seasonality of SARS-CoV remains unknown. SARS-CoV is not highly infectious, with generally only two to four secondary cases resulting from a single infected adult. During the SARS epidemic, a small number of infected individuals, “superspreaders,” transmitted infection to a much larger number of persons, but the mechanism for this high degree of spread remains unknown. In contrast, persons with mild disease, such as children younger than 12 yr of age, rarely transmitted the infection to others. Infectivity correlated with disease stage; transmission occurred almost exclusively during symptomatic disease. During the 2003 outbreak, most individuals with SARS-CoV infection were hospitalized within 3-4 days of symptom onset. Consequently, most subsequent infections occurred within hospitals and involved either healthcare workers or other hospitalized patients.

As of March 1, 2017, the WHO had recorded cases of MERS-CoV in 27 countries, all of which were linked to exposures in the Arabian peninsula (~80% in Saudi Arabia). Though the route of transmission between animals and humans is not fully understood, MERS-CoV is proposed to have repeatedly entered the human population through contact with respiratory secretions of dromedary camels and possibly with raw camel products (e.g., unpasteurized milk). Antibodies to MERS-CoV are found in dromedaries throughout the Middle East, and strains identical to human MERS-CoV isolates have been found in camels in Egypt, Oman, Qatar, and Saudi Arabia. These strains do not appear to be highly pathogenic or virulent in camels and have likely circulated within dromedaries for > 30 years. Despite well-documented zoonotic transmission, most reported cases occur through linked human-to-human transmission in healthcare settings, including outbreaks in Jordan, South Korea, and Saudi Arabia in 2015 and 2016. Risk factors for nosocomial MERS-CoV outbreaks include overcrowded emergency departments, delayed diagnosis or isolation, and poor infection control practices. Transmission most likely occurs through respiratory droplets and is thus a greater risk during aerosol-generating procedures. Outside of healthcare settings, human-to-human transmission has been infrequently documented and is primarily associated with close contact within households. No sustained human-to-human transmission has yet been reported.

Pathogenesis of SARS and MERS

Severe disease in SARS and MERS likely results from both direct virologic damage and subsequent immunopathology. Studies with SARS-CoV in human airway epithelial cell cultures indicate that ciliated cells are principal targets for infection, whereas MERS-CoV preferentially infects bronchial epithelial cells, type I and II pneumocytes, and vascular endothelial cells. Substantial viral loads can be detected in the lower respiratory tract and in blood for both viruses. However, late progression to severe disease appears independent of the quantity and timing of viremia. Thus, excessive host immune responses likely play an important role in the progression to lower respiratory disease and acute respiratory distress syndrome. CoV infections are associated with massive elaboration of inflammatory cytokines and recruitment of inflammatory cells. The roles for inflammatory cells are controversial, with cytotoxic T cells and macrophages implicated variously in immune protection and immunopathology. Recapitulation of human clinical features in animal models of MERS-CoV infection remains challenging, but promising new models are in development.